Stereoisomeric indole compounds, process for the preparation of the same, and use thereof

ABSTRACT

Novel stereoisomeric indole compounds of the formula (1), a process for the preparation the same, and use thereof                    
     wherein, Y represents the group                    
     wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkyl group may be substituted with hydroxyl group, carboxyl group, amino group, methylthio group, mercapto group, guanidyl group, imidazolyl group or benzyl group), and R 1  and R 2  represent each independently hydrogen atom, alkyl group, aralkyl group, cycloalkyl group or aryl group;R represents hydrogen atom, alkyl group, aralkyl group, cycloalkyl group, aryl group, monovalent metal, amine or ammonium; and the symbol ‘*’ represents a position of an asymmetric carbon atom. The above-mentioned compounds can be prepared by condensing tryptophan with a stereoisomeric α-amino acid or carboxylic acid to form an amide form and subjecting or carboxylic acid to form an amide form and subjecting the amide form to oxidative cyclization to form an oxazole ring at once. The compounds exhibit; physiological activities such as inhibitory action against lipid peroxidation, and can be therefore utilized in the form of lipid peroxidation inhibitors containing the same as the active ingredient.

This application is a 371 of PCT/JP98/03727 filed Aug. 24, 1998.

The present invention relates to novel stereoisomeric indole compoundsor salts therof, process for the preparation of the compounds and use ofthe compounds.

PRIOR ART

An indole compound (tartefragin A) of the following formula which isisolated from an extract of seaweed, “Ayanishiki”(Martensia fragilisHarvey) belonging to, Congregatocarpus family is known [Proceedings ofJapan Pharmaceutical Society, the 116^(th) annual meeting, page 2,215(1996)].

Further, the above-mentioned indole compound is known to have ananti-oxidative action and to have uses including pharmaceutical ones.However, a synthetic method and stereochemistry of the above-mentionedindole compound was not known.

The inventors of the present invention tried first to synthesizestereoisomers of the above-mentioned compound in order to clarifystereostructure, physiological activities and action mechanisms etc.thereof. As a synthetic route for the stereoisomers of the compound,they noticed a route for synthesizing the following L-tryptophan (2) anda stereoisomeric α-amino acid (3a′) (hereinafter, the stereoisomericα-amino acid is referred to as homoisoleucine) as intermediates.

(wherein, R, R₁ and R₂ have the meanings shown below, and the symbol ‘*’represents a position of asymmetric carbon atom.)

Since the stereoisomers of the above-mentioned homoisoleucine are notcommercially available compounds, they also established a syntheticroute described below for the stereoisomers of the homoisoleucine, andfurthermore they succeeded to synthesize a stereoisomeric indolecompound (1a′) from the above-mentioned L-tryptophan (2) and astereoisomeric homoisoleucine (3a′).

Further, from the fact that the synthetic route for the stereoisomericindole compound (1a′) from the above-mentioned L-tryptophan (2) and thestereoisomeric homoisoleucine (3a′) was established, in the same manneras in the stereoisomeric homoisoleucine, novel indole alkaloids could besynthesized from L-tryptophan and various α-amino acids other than thestereoisomeric homoisoleucine as starting materials for the purpose ofsearching compounds having stronger physiological activities than thoseof the above-mentioned compound (1a′), thus many compounds was obtained.

The inventors also have found that a deamino form of the above-mentionedcompound (1a′) has higher inhibitory action against lipid peroxidationthan any of the four isomers of the above-mentioned Martefragin A, thatis (1″S,3″S) form, (1″R,3″S) form, (1″R,3″R) form and (1″S,3″R) form,and also have established synthetic routes thereof.

DISCLOSURE OF THE INVENTION

That is, the present invention relates to stereoisomeric indolecompounds of the following formula (1) or salts thereof.

wherein, Y represents the group:

wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkylgroup may be optionally substituted with hydroxyl group, carboxyl group,amino group, methylthio group, mercapto group, guanidyl group,imidazolyl group or benzyl group), and R₁ and R₂ represent eachindependently hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup or aryl group, or Y represents the group

R represents hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup, aryl group, monovalent metal atom, amine or ammonium; and thesymbol ‘*’ represents a position of an asymmetric carbon atom.

Specifically, there may be mentioned the compound of an amino form ofthe formula (1a):

or salts thereof as well as the compound of a deamino form of thecompound of the formula (1a) of the formula (1b) or salts thereof

wherein, R, R¹, R₂ and X have the same definitions as the formula (1)

In compounds of the above-mentioned formulae (1), (1a) and (1b),specific examples of suitable substituents are as follows.

In addition to the fact that the substituent R represents hydrogen atom,typical substituents R are straight chained or branched alkyl grouphaving 1-12, particularly 1-6, carbon atom(s), such as methyl group,ethyl group, propyl group, isopropyl group, n-butyl group, tertiarybutyl group, pentyl group, hexyl group, octyl group, decyl group anddodecyl group; cycloalkyl group having 5 or 6 ring carbon atoms, such ascyclopentyl group, methylcyclopentyl group, cyclohexyl group andmethylcyclohexyl group; aryl group having 6-16 carbon atoms and aralkylgroup having 7-16 carbon atoms, such as phenyl group, naphthyl group,benzyl group and phenylethyl group, which may be substituted withhalogen atom, hydroxyl group, alkoxy group, amino group and so on.Further, the substituent R may be monovalent metal such as sodium andpotassium, amine or ammonium.

Further, suitable substituents R₁ and R₂ are straight chained orbranched alkyl group having 1-12, particularly 1-6, carbon atom(s), suchas methyl group, ethyl group, propyl group, isopropyl group, n-butylgroup, tertiary butyl group, pentyl group, hexyl group, octyl group,decyl group and dodecyl group; cycloalkyl group having 5 or 6 ringcarbon atoms, such as cyclopentyl group, methylcyclopentyl group,cyclohexyl group and methylcyclohexyl group; aryl group having 6-16carbon atoms and aralkyl group having 7-16 carbon atoms, such as phenylgroup, naphthyl group, benzyl group and phenylethyl group, which may besubstituted with halogen atom, hydroxyl group, alkoxy group, amino groupand so on.

As the salts of the compounds of the formulae (1), (1a) and (1b), thereare exemplified salts of inorganic acids and organic acids. However,hydrochloride are particularly preferable.

The indole compounds according to the present invention have one or moreasymmetric carbon atom(s), thus form or R form isomers occur dependingupon the positions) thereof. For example, in the case of an amino formof the compound (1a′),

it has asymmetric carbon atoms at positions 1″ and 3″. Therefore, thecompounds according to the invention have four isomers respectively fortheir asymmetric carbon atoms, i.e., (1″S,3″S) form, (1″R,3″S) form,(1″R,3″R) form, (1″S,3″R) form. Further, a deamino form (1b)

of the indole compound according to the invention has an asymmetriccarbon atom at position 3″. Therefore, the compounds according to theinvention have two isomers respectively for their asymmetric carbonatoms, i.e., S form and R form.

The present invention includes all these isomers and mixtures of theisomers.

In the following illustration, the indole compound of theabove-mentioned formula (1b) is also referred to as“deaminomartefragin”.

The present invention also relates to a process for preparing thestereoisomeric indole compounds of the following formula (1)

by condensing tryptophan of the following formula (2)

with an acid of the following formula (3)

to obtain a compound of the following formula (4),

and subjecting the compound of the formula (4) to cyclization,

wherein, Y represents the group

wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkylgroup may be substituted with hydroxyl group, carboxyl group, aminogroup, methylthio group, mercapto group, guanidyl group, imidazolylgroup or benzyl group), and R¹ and R² represent each independentlyhydrogen atom, alkyl group, aralkyl group, cycloalkyl group or arylgroup, or Y represents the group

R represents hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup, aryl group, monovalent metal atom, amine or ammonium; and thesymbol ‘*’ represents a position of an asymmetric carbon atom.

According to this method, the amino form of the stereoisomeric indolecompound of the above-mentioned formula (1a) can be prepared bycondensing tryptophan of the above-mentioned formula (2) with an acid ofthe formula (3a)

to obtain a compound of the following formula (4a),

and subjecting the compound of the formula (4a) to cyclization, and thedeamino form of the stereoisomeric indole compound of theabove-mentioned formula (1b) can be prepared by condensing tryptophan ofthe above-mentioned formula (2) with an acid of the following formula(3b)

to obtain a compound of the following formula (4b),

and subjecting the compound of the formula (4b) to cyclization, wherein,R, R₁, R² and X have the above-mentioned meanings.

In the compounds of the above-mentioned formulae (2)-(4), (2a)-(4a) and(2b)-(4b), specific examples of suitable substituents are same as thosementioned for the formulae (1), (1a) and (1b).

As described above, the acid used for synthesis of the stereoisomericindole compounds according to the invention is a stereoisomeric α-aminoacid in the case of preparing an amino form and also 4-methylhexanoicacid which is a stereoisomeric carboxylic acid in case of preparing adeamino form.

Typical stereoisomeric α-amino acids include, for example, fourstereoisomers of (+)alanine, (+)valine, (−) leucine, (+)isoleucine,(+)lysine, (−)serine, (−)threonine, (−)phenylalanine, (−)tyrosine,(−)aspartic acid, (+)glutamic acid, (−)methionine, (+)arginine,(−)histidine, (+)ornithine, (+)norleucine, (+)oxyglutamic acid,(−)cysteine and homoisoleucine. Note that four stereoisomers ofhoxnoisoleucine are not commercially available, and their syntheticexamples are shown below in I. Preparation Examples 1-4 for amino formsof stereoisomeric indole compounds.

4-Methylhexanoic acid has two isomers, which are obtained respectivelyas intermediates in a synthetic route for (2S,4S)-homoisoleucine in thePreparation Example I and in a synthetic route for(2S,4R)-homoisoleucine in the Preparation example 3 described below.

According to the invention, a stereoisomeric indole compound is preparedby (1) condensing tryptophan with a stereoisomeric α-amino acid or4-methylhexanoic acid to form an amide, and then (2) subjecting theamide to oxidative cyclization to form an oxazole ring at once by anovel synthetic method For condensation of the tryptophan with thestereoisomeric α-amino acid or 4-methylhexanoic acid, it is preferableto protect an amino group of the α-amino acid. Although there may bementioned dialkylatione preferably dimethylation, t-butoxycarbonylationand so on for protection of the amino group, it is preferable that whenthe protecting group being t-butoxycarbonyl group (Boc group) because,particularly, condensation of tryptophan with the stereoisomeric α-aminoacid and the subsequent cyclization of the amide are proceededefficiently.

Further, if the oxidative cyclization of the amide is carried outparticularly in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone(DDQ), the cyclization is proceeded efficiently to obtain the cyclizedform in a high yield.

For the compounds of the formula (1) according to the invention, it ispossible to obtain various kinds of compounds by varying the group Yaccording to selection of raw materials, i.e., a stereoisomeric α-aminoacid and a carboxylic acid, and by varying the substituents R, R₁ and R₂according to selection of ester group in the raw material, i.e.,tryptophan ester, and selection of the amino substituent of thestereoisomeric α-amino acid, or by changing the substituents in thecompounds after synthesis with other substituents R, R₁ and R₂ differentfrom those.

The novel stereoisomeric indole compounds according to the invention arealkaloids having an indole ring and an oxazole ring, which haveinhibitory action against lipid peroxidation, and can be thereforeutilized as preventing drugs and therapeutic drugs for circulatorydisorders such as arteriosclerosis, hypertension, thrombosis;inflammations such as nephritis; hepatic disorders such as alcoholichepatitis; digestive disorders such as gastric ulcer; diabetes,carcinogenesis and senescence as well as ultraviolet disorders, and alsoutilized as ultraviolet disorder preventing materials in cosmetics andthe like.

Therefore, the present invention furthermore relates to lipidperoxidation inhibitors containing as the active ingredient thestereoisomeric indole compounds or their salts which are of theabove-mentioned formula (1) and exemplified by the formulae (1a) and(1b).

BEST MODE FOR CARRYING OUT THE INVENTION I. Synthesis For Amino Forms ofStereoisomeric Indole Compounds (Martefragin A and salts or estersthereof)

Synthetic examples of amino forms of indole compounds according to theinvention are illustrated as follows. Before synthesis for the compoundsaccording to the invention, syntheses for stereoisomeric homoisoleucinewhich is raw materials are illustrated in Preparation Examples 1-4, andsynthetic examples for stereoisomeric indole compounds by using them areillustrated in Examples

PREPARATION EXAMPLE 1 Synthesis of (2S,4S)-homoisoleucine

(2S,4S)-homolsoleucine can be synthesized from optically activemethylbutanol or optically active methyliodobutane as startingmaterials.

1. Tosylation of optically active methylbutanol (step 1 in Scheme 1)

1 g (11.3 mmol) of (S)-2-methyl-1-butanol: (S)-1 (Tokyo Kasei) and 30 mlof anhydrous pyridine are added into a 100 ml egg plant type flask underan argon atmosphere and stirred at 0° C., and thereafter 4.31 g (22.6mmol) of p-toluenesulfonyl chloride is added and stirred at 0° C. for 30minutes, and then stirred at room temperature for 5 hours. Ice water isadded and an aqueous layer is adjusted to pH 2-3 with 3N hydrochloricacid and then extracted with diethyl ether. After it is washed with asaturated sodium hydrogencarbonate solution and a saturated salinesolution, dried with anhydrous magnesium sulfate, and distilled off thesolvent under a reduced pressure, to obtain a colorless oily substance.It is purified with a column chromatography (75 g of SiO₂, hexane/ethylacetate=10:1), to obtain 2.5 g of a tosylated form (S)-2 (a colorlessoily substance: yield; 91.41).

C₁₂H₁₈SO₃ (M.W.; 242.10), a colorless oily substance, [α]_(n) ²⁰+5.66(C=1.060, MeOH)

2. Iodation of tosylated form (S)-2 (step 2 in Scheme 1)

1.94 g (S mmol) of the tosylated form (S)-2 and 30 ml of anhydrousacetone are added into a 100 ml egg plant type flask under an argonatmosphere, shielded from light, and thereafter 2.4 g (16 mmol) ofsodium iodide is added. After stirring at room temperature for 2 days,pentane is added to dilute the reaction solution and cooled toprecipitate its sodium salt. After the sodium salt is removed with aglass filter, it is extracted with water to remove acetone, dried withanhydrous magnesium sulfate and distilled off pentane under the normalpressure, to obtain 1.08 g (yield; 68.0%) of an iodated form (S)-3. Thestructure thereof is confirmed by comparison with a commerciallyavailable one.

3. Synthesis of ester malonate using iodated form (S)-3 (step 3 inScheme 1)

1.38 g of metallic sodium and 50 ml of anhydrous ethanol are added intoa 200 ml three-necked flask under an argon atmosphere at 0° C. andstirred. After sodium is all dissolved, 9.45 ml of diethyl malonate isadded dropwise by a syringe, and then 6.5 ml of the iodated form (S)-3is added dropwise and stirred at room temperature overnight. 100 ml ofan aqueous ammonium chloride solution is added, ethanol is removed bydistillation under a reduced pressure, and the residue is extracted withdiethyl ether. An ether layer is washed with a saturated salinesolution, thereafter dried with anhydrous magnesium sulfate, anddistilled off the solvent under a reduced pressure, to obtain acolorless oily substance, It is purified with a column chromatography(200 g of SiO₂ for flash, hexane/ethyl acetate 30:1), to obtain 8.80 g(yield; 76.5%) of a diester form (S)-4.

C₁₂H₂₂O₄ (M.W.; 230.15), a colorless oily substance, [α]_(D) ²+15.3(C=1.060, MeOH)

4. Hydrolysis of diester form (S)-4 (step 4 in Scheme 1)

6.90 g of the diester form (S)-4 and 20 ml of ethanol are added into a300 ml egg plant type flask and stirred. 5.71 g (102 mmol) of potassiumhydroxide dissolved beforehand in 100 ml of water is added and heated atreflux. The temperature of the solution is returned to room temperatureand ethanol is removed by distillation under a reduced pressure, andthereafter impurities are removed by extraction with ethyl acetate.After 3N HCl is added to an aqueous layer to adjust to pH 1-2, the layeris extracted with ethyl acetate. An organic layer is salted out withsodium chloride, dried with anhydrous magnesium sulfate and thereafterdistilled off the solvent under a reduced pressure, to obtain 5.22 g(yield; 100%) of an intended compound, a dicarboxylic acid (S)-5.

C₈H₁₄O₄ (M.W.; 174.09), white powders, [α]_(D) ²⁶+16.9 (C=1.10, MeOH)

5. Decarboxylation of dicarboxylic acid (S)-5 (step 5 in Scheme 1)

5.05 g (29 mmol) of the dicarboxylic acid (S)-5, 16 ml of a 7% aqueousDMSO solution and 1.87 g (32 mmol) of sodium chloride are added into a50 ml egg plant type Cask, and heated at 150-175° C. for 4 hours. Thetemperature of the solution is returned to room temperature andextracted twice with diethyl ether, and an organic layer is washed withwater. It is dried with anhydrous magnesium sulfate and distilled offthe solvent under a reduced pressurer to obtain a colorless oilysubstance. It is purified with a column chromatography (120 g of SiO₂,pentane/diethyl ether=5:1), to obtain 2.82 g (yield; 75%) of an intendedcarboxylic acid (S)-6. The (S)-6 is a raw material for synthesis ofdeaminomartefragin described below.

C₇H₁₄O₂ (M.W.; 130.10), colorless and oily, [α]_(D) ²⁶+9.69 (C=1.042,MeOH)

6. Synthesis of acid chloride (S)-7 (step 6 in Scheme 1)

2.82 g of the carboxylic acid (S)-6, 18.0 ml of anhydrous benzene and9.0 ml of thionyl chloride are added into a 50 ml egg plant type flaskand heated at reflux for 3 hours. The temperature of the solution isreturned to room temperature and thereafter distilled off the solventunder a reduced pressure, to obtain 2.92 g (yield; 91%) of an acidchloride (S)-7. The (S)-7 is subjected to condensation with anasymmetrical assistant group (S)-8 without any purification afterconfirming absorption of the carbonyl group assigned to the acidchloride by IR spectrum. C₇H₁₃Cl (M.W.; 148.55), colorless and oily.

7. Condensation with asymmetic assistant group (S)-8 (step 7 in Scheme1)

3.85 g (21.7 mmol) of (4S)-benzyloxazolidinone and 50 ml of anhydrous(THF) are added into a 200 ml three-necked flask under an argonatmosphere and cooled to −78° C. 13.6 ml of a 1.6M n-butyllithium/n-hexane solution is added and stirred at −78° C. for 40minutes, and 2.92 g (19.7 mmol) of the acid chloride (S)-7 is added andstirred at −78° C. for 1.5 hours. An aqueous ammonium chloride solutionis added, and the solution is extracted with diethyl ether, washed witha saturated saline solution, dried with anhydrous magnesium sulfate, andthereafter distilled off the solvent under a reduced pressure, to obtaina colorless oily substance. It is purified with a column chromatography(45 g of SiO₂, hexane/ethyl acetate=5:1), to obtain 4.93 g (yield;86.5%) of an intended compound (S)-9, as colorless crystals.

C₁₇H₂₃NO₃ (M.W.; 289.29), white powders, [α]_(D) ²⁷+59.3 (C=1.088,CHCl₃)

8. Direct azidation to carboxyimide (step 8 in Scheme 1)

1.03 g (5.19 mmol) of potassium ditrimethylsilylamide and 10 ml ofanhydrous THF are added into a 100 ml two-necked flask under an argonatmosphere and made to −78° C. 1 g (3.46 mmol) of (S)-9 dissolvedbeforehand in 10 ml of anhydrous THF is added by a cannula and stirredat −78° C. for 30 minutes. Furthermore, 1.35 g (4.36 mmol) oftriisopropyl benzenesulfonylazide dissolved beforehand in 6 ml ofanhydrous THF is added by a cannula and stirred for 2 minutes, andthereafter 0.91 ml (15.9 mmol) of glacial acetic acid is added. It isstirred at room temperature for 7 hours. The reaction solution isdiluted with ethyl acetate, to which a saturated saline solution isadded and extracted twice with ethyl acetate. It is washed with asaturated sodium hydrogencarbonate, dried with anhydrous sodium sulfate,and distilled off the solvent under a reduced pressure, to obtain 1.85 gof a yellow oily substance. It is purified with a column chromatography(60 g of SiO₂. for flash, hexane/dichloromethane=3:1), to obtain 893 mg(yield; 78.1%) of an intended azide form (2S, 4S)-10.

C₁₇H₂₂N₄O₃ (M.W.; 330.39), colorless crystals, mp.; 71.5-72.5° C.,[α]_(D) ²⁴+112.2 (C=1.032, CHCl₃)

9. Removal of asymmetrical assitant group [Synthesis of α-azidecarboxylic Acid (2S, 4S-11] (step 9 in Scheme 1)

850 mg of the azide form (2S, 4S)-10 and 50 ml of 75% THF are added intoa 200 ml egg plant type flask under an argon atmosphere and made to 0°C., and 216 mg of lithium hydroxide monohydrate is added and stirred for1 hour. An aqueous saturated sodium hydrogencarbonate solution is added,distilled off THF under a reduced pressure, and thereafter extractedwith ethyl acetate. An ethyl acetate layer is dried with anhydroussodium sulfate and distilled off the solvent under a reduced pressure,to recover 450 mg (yield; 99%) of (S)-8. An aqueous layer is adjust topH 1-2 with 3N hydrochloric acid and extracted with ethyl acetate, andan ethyl acetate layer is dried with anhydrous sodium sulfate anddistilled off the solvent under a reduced pressure, to obtain 425 mg(yield; 96.7%) of an intended α-azide carboxylic acid (2S,4S)-11 as ancolorless oily substance.

C₇H₁₃N₃O₂ (M.W.; 171.101), a colorless oily substance, [α]_(D) ²³+3.26(C=0.982, CHCl₃)

10. Reduction of α-azide carboxylic acid: Synthesis of(2S,4S)-homoisolencine (step 10 in Scheme 1)

378 mg (2.21 mmol) of the α-azide carboxylic acid (2S,4S)-11, 4.0 ml ofanhydrous ethanol and 37.8 mg of 10% Pd-C are added into a 25 ml eggplant type flask under an argon atmosphere with hydrogen displacementand stirred at room temperature for 2.5 hours. Pd-C is removed byfiltration and the solvent is distilled off under a reduced pressure, toobtain 285 mg (yield; 88.9%) of (2S,4S)-12 [(2S,4S)-homoisoleucine] ascolorless crystals.

C₇H₁₅NO₂ (M.W.; 145.1103), colorless crystals, IR: ν [cm⁻]=2962, 2920,1584, 1513, 1405, 669, 554, 471 LREIMS: m/z (%) 154(M⁺, 1), 100(100)HREIMS Calcd for C₇H₁₅NO₂: 145.1103, Found 145.1127

PREPARATION EXAMPLE 2 Synthesis of (2R,4S)-homoisoleucine

The steps to the acid chloride (S)-7 are the same as the above-mentionedPreparation Example 1. The asymmetrical assistant group used hasR-configuration. The reaction steps after the condensation with theasymmetrical assistant group are carried out similarly to PreparationExample 1. The reaction steps from the condensation with theasymmetrical assistant group to synthesis of (2R,4S)-homoisoleucine[(2R,4S)-23] and physical data for (2R,4S)-homoisoleucine are shown asfollows.

PREPARATION EXAMPLE 3 Synthetic route of (2S,4R)-homoisoleucine

(2S,4R)-homoisoleucine is synthesized from (S)-citronellol as a startingmaterial.

1. Mesylation of (S)-citronellol (step 1 in Scheme 3)

5 g (32.0 mmol) of (5)-citronellol, 180 ml of dichloromethane and 4.86 g(35.2 mmol, 1.1 eq) of triethylamine are added into a 500 mlthree-necked flask under an argon atmosphere and cooled with ice to −10°C., and thereafter 4.03 g (35.2 mmol, 1.1 eq) of mesyl chloride is addeddropwise. After the reaction solution is stirred at −10 to 0° C. for 2.5hours, it is washed with ice water, 5% hydrochloric acid and water,dried with anhydrous sodium sulfate and distilled off the solvent undera reduced pressure, to obtain a colorless oily substance (S)-30. It issubjected to the next reduction without any purification.

2. Reduction of mesylate (S)-30 (step 2 in Scheme 3)

400 ml of diethyl ether and 1.80 g (47.3 mmol, 1.4 eq) of lithiumaluminum hydride are added into a 200 ml three-necked flask equippedwith a calcium chloride tube and a reflux condenser and cooled with ice.A solution of 7.92 g (33.8 mmol) of (S)-30 in diethyl ether is addeddropwise and heated at reflux for 3 hours. After completion of thereaction, the reaction solution is cooled with ice, and 3.6 ml of wateris added and stirred for 1 hour, additional 2.88 ml of a 10% aqueoussodium hydroxide solution is added and stirred for 1 hour thereafterfiltered off by Celite to remove lithium aluminum hydride and distilledoff the solvent under a reduced pressure, to obtain 4.5 g (98%) of acolorless oily substance (R)-31.

3. Oxidation of (R)-31 (step 3 in Scheme 3)

24.7 g (115.6 mmol, 3.6 eq) of sodium periodate and 175 ml of an aqueousacetone solution (acetone:water=70:105) are added to suspend in a 500 mlthree-necked flask under an argon atmosphere. A solution of 4.5 g (32.1mmol) of (R)-31 in acetone is added dropwise and made to 5° C. 40 ml ofa solution of 0.86 g (5.46 mmol, 0.17 eq) of potassium permanganate inwater and 40 ml of acetone are added dropwise simultaneously. They arestirred at from 5° C. to room temperature for 20 hours. A reddish brownresidue is removed by filtration with Celite, and acetone is distilledoff under the normal pressure. 1N sodium hydroxide is added to theresidue to make basic, which is extracted with diethyl ether to removesolubles. An aqueous layer is acidified with 3N hydrochloric acid,extracted with diethyl ether, dried with anhydrous sodium sulfate anddistilled off the solvent under a reduced pressure, to obtain acolorless oily substance. It is purified with a column chromatography(50 g of SiO₂, hexane/ethyl acetate=5:1), to obtain 2.389 g (57%) of(R)-32. The (R)-32 is a raw material for synthesis of deaminomartefragindescribed below.

4. Steps (4)-(8) in Scheme 3

Steps (4)-(8) in Scheme 3 are carried out similarly to steps (6)-(10) inPreparation Example 1. Physical data of the obtained(2S,4R)-homoisoleucine [(2S,4R)-37] are as follows.

IR (neat): v [cm⁻¹]=2964, 1587, 1404

PREPARATION EXAMPLE 4 Synthesis of (2R,4R)-homoisoleucine

Steps to the acid chloride (R)-33 are same as the above-mentionedPreparation Example 3. The steps after the condensation with anasymmetric assistant group by using R-configuration asymmetric assistantgroup are carried out similar to the Preparation Example 1.

The steps from the condensation with the asymmetrical assistant group tosynthesis of (2R,4R)-homoisoleucine [(2R,4R)-47] and physical data for(2R4R)-homoisoleucine are shown as follows.

Next, synthetic examples of stereoisomeric indole compounds fromtryptophan ester and stereoisomeric homoisoleucine are shown.

EXAMPLE 1 Synthesis of (1″S,3″S)-indole

1. t-Butoxycarbonylation of (2S, 4S)-homoisolenine (step 1 in Scheme 5)

1285 mg (1.96 mmol) of (2S,4S)-homoisoleucine obtained in PreparationExample 1, 2.5 ml of a 1N aqueous sodium hydroxide solution, 1.5 ml ofwater, 1.5 ml of dioxane and 643 mg (2.95 mmol) of Boc₂O are added intoa 25 ml egg plant type flask and stirred at room temperature for 16hours. An aqueous saturated sodium hydrogencarbonate solution is addedand washed with diethyl ether, and thereafter an aqueous layer isacidified (to about pH3) and extracted twice with diethyl ether. It iswashed with water, dried with anhydrous sodium sulfate and distilled offthe solvent under a reduced pressure, to obtain 456 mg (yield; 95%) of(2S,4S)-13 ) Boc form of (2S,4S)-homoisoleucine as a colorless oilysubstance.

IR (neat) ν [cm⁻¹]=2965, 1724, 1516, 1456, 1252, 1165, 1051, 1024, 852,779.

2. Condensation of tryptophan-O-benzyl ester and Boc form of(2S,4S)-homoisoleucine (step 2 in Scheme 5)

325 mg of L-tryptophan benzyl ester, 30 ml of anhydrous THF and 265 mgof the Soc form of homoisolencine [(2S,4S)-13] are added into a 100 mltwo-necked egg plant type flask under an argon atmosphere and made to 0°C. 0.3 ml of a condensing agent, DEPC (diethylphosphoryl cyanide) and0.33 ml of triethylamine are added dropwise by a syringe and stirred at0° C. for 1 hour, then at room temperature for 1 hour. Ethyl acetate isadded, dried with saturated sodium hydrogencarbonate and distilled offthe solvent under a reduced pressure, to obtain a brown oily substance.It is purified with a column chromatography (20 g of SiO₂, hexane/ethylacetate=2:1), to obtain 493.7 mg (yield; 97%) of an intended condensate,dipeptide-15, as a amorphous state. It is recrystallized from ethylacetate and hexane.

IR(KBr): ν [cm⁻¹]=3365, 2962, 1734, 1684, 1647, 1520, 1458, 1437, 1275,1256 1160, 741

¹³C-NMR (400 MHz, CDCl₃): 172.15(s), 171.42(S). 155.44(s), 13624(s),135.32(s),

128.50(s), 128.32(s), 127.72(s), 123.07(s), 122.19(s),

119.67(s), 118.65(s), 111.23(s), 109.84(s), 80.01(s),

67.13(s), 53.08(s), 39.59(s), 30.07(s), 28.70(s), 28.29(s),

27.79(s), 19.27(s), 10.84(s)

LRFABMS: m/z(%) 522(M+H⁺, 20), 130(100)

HRFABMS Calcd for C₃₀H₃₉N₃O₅+H: 522,2968. Found: 522.2957

¹H-NMR (400 MHz, CDCl₃): δ 8.14 (1H, b, 1—H)

δ 751 (1H, d, J=7.6, 7—H)

δ 7.28˜6.85 (9H, m, Aromatic Hs)

δ 652 (1H, d, 2—H)

δ 5.04 (2H, s, 4′—H)

δ 4.93 (1H, m, 2′—H)

δ 4.82 (1H, b, 9″—H)

δ 4.07 (1H, s, 3″—H)

δ 3.29 (2H, m, 1′—H)

δ 1.72 (1H, m, 5″—H)

δ 1.40 (9H, s, BOC—Hs)

δ 1.28 (2H, m, 4″—H)

δ 1.07(1H, m,)

δ 0.84 (6H, m, 6″—H, 7″—H)

3. DDQ oxidation of dipeptide-15 (step 3 in Scheme 5)

300 mg (0.60 mmol) of dipeptide-15, 30 ml of anhydrous THF and 313 mg(1-38 mmol) of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) are added intoa 100 ml egg plant type flask under an argon atmosphere and heated atreflux for 1 hour. The temperature of the solution is returned to roomtemperature and distilled off THFunder a reduced pressure, andthereafter water is added and extracted with ethyl acetate. An ethylacetate layer is washed with an aqueous saturated sodiumhydrogencarbonate solution and a saturated saline solution and driedwith anhydrous magnesium sulfate. The solvent is distilled off under areduced pressure, to obtain a brown solid. It is purified with a columnchromatography (10 g of SiO₂ for flash, hexane/ethyl acetate=3:1), toobtain 224 mg (yield; 62.5%) of an intended cyclized form 1″S,3″S)-16.

IR (KBr): ν[cm⁻¹=]3278, 2964, 1689, 1593, 1280, 1245, 1188, 1074, 741,696

¹H-NMR (400 Mhz, CDCl₃): δ 8.66 (1H, b, 1′N—H)

δ 8.60 (1H, s, 2′—H)

δ 8.13 (1H, d, J=7.8, 7′—H)

δ 7.45 (3H, m, 4′˜6′—H)

δ 7.24-738 (5H, m, —Ph)

δ 5.32 (2H, dd, J=12.5, 16.4, —CH₂Ph)

δ 5.28 (1H, d, 1″—H)

δ 5.10 (1H, d, N—H)

δ 1.74 (1H, m, 2″—H)

δ 1.52 (2H, m. 4″—H)

δ 1.45 (9H, s, BOC—H)

δ 1.22 (1H, m, 3″—H)

δ 0.99 (3H, d, J=6.6, 6″—H)

δ 0.88 (3H, t, 1J=7.3, 5″—H)

LRFASMS: m/z(%) 518(M⁺+H, 100)

HRFABMS Calcd for C₃₀H₃₅N₃O₅+K 518.2655. Found: 518.2639

Anal. Calcd For C₃₀H₃₉N₃O₅: C69.6, HB6.8Z, N8.12 Found: C68.35, H6.83,N7.74

4. De-t-butoxycarbonylation of cyclized form (1″S,3″S)-16 (step 4 inScheme 5)

16.80 mg (0.15 mmol) of the cyclized form (1″S,3″S)-16 and 2 ml ofdichloromethane are added into a 30 ml two-necked flask under an argonatmosphere and cooled to 0° C. 0.5 ml of trifluoroacetic acid is added,stirred at 0° C. for 1 hour, and thereafter stirred at room temperatureuntil the raw materials being disappeared. It is cooled again to 0° C.and neutralized with an aqueous saturated sodium hydrogencarbonatesolution, removed off the solvent by distillation under a reducedpressure and extracted with ethyl acetate. An organic layer is washedwith an aqueous saturated sodium chloride solution, dried with anhydroussodium sulfate and thereafter distilled off the solvent under a reducedpressure, to obtain 59 mg (yield; 91%) of an amine form (1″S,3″S)-17 asa brown solid. It is recrystallized from ethyl acetate ester and hexane.

IR (KBr): ν [cm⁻¹]=3143, 2962, 1707, 1593, 1280, 1244, 1074, 741, 698

¹H-NMR (400 Mhz CDCl₃): δ 9.20 (1H, b, 1′N—H)

δ 8.67 (1H, d, J=2.7, 3′—H)

δ 8.11 (1H, m, 7′-H)

δ a 7.42 (3H, m, 4˜6′—H)

δ 7.29 (5H, m, —Ph)

δ 5.42 (2H, s, —CH₂Ph)

δ 4.26(1H, b, 1′—H)

δ 2.03(1H, m, 2′—H)

δ 1.76(2H, b, N—H)

δ 1.69 (1H, m, 4″—H)

δ 1.51 (H, m, 4″—H)

δ 1.21 (1H, m, 3″—H)

δ 0.97 (3H, d, J=6.6, 6″—H)

δ 0.87 (3H, t 7.5, 5″—H)

LRFABMS: m/z(%) 417(M⁺, 85), 401(100)

HRFABMS Cald for C₂₅H₂₇N₃O₃+H: 418.2131. Found: 418.2115

Anal. Calcd for C₂₅N₃O₃: C71.92, H6.52, N10.06 Found C71.99, H6.62,N10.25

5. Dimethylation of amine form (1″S,3″S)-17 (step 5 in Scheme 5)

85 mg (0.20 mmol) of the amine form (1″S,3″S)-17, 3.4 ml of a 37%formaldehyde solution, 1.7 ml of acetic acid and 3.0 ml of 1,4-dioxaneare added into a 25 ml egg plant type flask under an argon atmosphereand also 85 mg of 10% Pd-C is added with ice cooling. Hydrogendisplacement is carried out and stirring is continued at roomtemperature until the raw materials being disappeared (about 1.5 hours).Ethanol is added, Pd-C is removed by filtration, and the solvent isdistilled off under a reduced pressure, to obtain 466 mg of a colorlessoily substance It is purified with a column chromatography (15 g ofsilica gel for flash, hexane/ether=1:5), to obtain 4.7 mg (yield; 53%)of a dimethyl form (1″S,3″S)-18 as a colorless oily substance.

IR (neat): v (cm⁻¹=330, 2962, 1701, 1589, 742, 702

¹H-NMR(400 MHz, CDCl₃): δ 9.36 (1H, b, 1′N—H)

δ 8.71 (1H, d, J=2.9, 2′—H)

δ 8.16 (1H, m, 7′—H)

δ 7.42 (3H, m, 4′-6′—H)

δ 7.28 (5H, m, —Ph)

δ 5.42 (2H, dd, J=12.4, 163, —CH₂Ph)

δ 4.01 (1H, dd, J=5.3, 9.7. 1″—H)

δ 2.39 (6H, s, N(CH₃)₂)

δ 2.21 (1H, m, 2″—H)

δ 1.72 (1H, m, 2″—H)

δ 1.39 (1H, m, 4″—H)

δ 1.26 (1H, m, 4″—H)

δ 1.19 (1H, m, 3″—H)

δ 0.93 (3H, d, J=6.6, 6″—H)

δ 0.84 (3H, t, J=7.3. 5″—H)

LAFABMS: m/z(%) 446(M⁺+H, 15), 401(100)

HRFABMS Calcd for C₂₇H₃₁N₃O₃+H: 446.2444 Found 446.2449

6. Debenzylation of dimethyl form (1″S,3″S)-18 (step 6 in Scheme 5)

44 mg (0.0988 mmol) of the dimethyl form (1″S,3″S)-18 and 4 ml of ethylacetate are added into a 25 ml egg plant type flask under an argonatmosphere and cooled with ice, and 44 mg of 10% Pd-C is added. Hydrogendisplacement is carried out and stirring is continued at roomtemperature until the raw materials being disappeared. Ethanol is addedand Pd-C is removed by filtration, and the solvent is distilled offunder a reduced pressure, to obtain a colorless solid. It is purifiedwith a column chromatography (1 g of SiO₂, CHCl₃/MeOH/NH₄H=7:3:03), toobtain 10 mg (yield; 57.4%) of (1″S,3″S)-19.

IR(KBr): ν [cm⁻¹]=3430, 2962, 1595, 1458, 1389, 744

¹H-NMR (400 MHz, CDCl₃): δ 8.60 (1H, b, 2′—H)

δ 8.01 (1H, d, 7′—H)

δ 7.33 (1H, dd, J=1.0, 7.6, 4′—H)

δ 7.05 (2H, m, 5′, 6′—H)

δ 4.24 (1H, dd, J=4.5, 11.0, 1″—H)

δ 2.36 (1H, ddd, J=10.5. 10.5, 2.7)

δ 1.74 (1H, m 2″—H)

δ 1.36 (1H, m, 4″—H)

δ 1.26 (1H, m, 3″—H)

δ 1.18 (1H, m, 4″—H)

δ 0.96 (3H, d, J=6.4, 6″—H)

δ 0.84(3H, t, J=7.1, 5,″—H)

EXAMPLE 2 Synthesis of (1″R,3″S)-indole

Similar to Example 1, (1″R,3″S)-indole is prepared from tryptophan esterand (2R,4S)-homoisoleucine in the Preparation Example 2. The syntheticroute thereof is illustrated as follows.

Physical data for respective compounds are shown as follows.

(Compound 25)

¹H-NMR (400 Mhz, CDCl₃): δ 7.99 (1H, b, 1N—H)

δ 7.52 (1H, d, J=7.3, 7—H)

δ 7.20 (9H, m, Aromatic Hs)

δ 6.85 (1H, s, 2—H)

δ 6.65 (1H, b, 1N—H)

δ 5.06 (2H, s, 4′—H)

δ 4.93 (1H, d, J-7.5, 2′—H)

δ 4.70 (1H, b, 9″—H)

δ 4.12 (1H, q, J=7.0, 3″—H)

δ 3.32 (2H, m, 1″—H)

δ 1.58 (1H, dd, J=4.1, 12.9, 5″—H)

δ 1.47 (2H, m, 6″—H)

δ 1.40 (9H, s, BOC—Hs)

δ 1.25 (1H, t, J=7.0, 4″—H)

δ 1.16 (1H, f, J=7.0, 4″—H)

δ 0.84 (3H, d, J=6.6, 8S″—H)

δ 0.83 (3H, t, J=7.5, 7″—H)

(1″R, 3″S)-26

¹H-NMR (400 Mhz, CDCl₃): δ 8.67 (1H, b, 1′N—H)

δ 8.53 (1H, s, 2′—H)

δ 8.14 (1H, d, J=7.9. 7′—-H)

δ 7.24-7.48 (8H, m, Aromalic Hs)

δ 5.29 (2H, dd, J=11.9, 17.0, —CH₂Ph)

δ 5.12 (1H, m, 1′—H)

δ 5.10 (1H, b, N—H)

δ 1.87 (2H, m, 2″—H)

δ 1.53 (2H, m, 4″—H)

δ 1.46 (9H, s, BOC—Hs)

δ 1.28 (1H, m, 3″—H)

δ 0.99 (3H, d, J=6.6, 6″—H)

δ 0.91 (3H, t, J=7.5 5″-H)

(1″R, 3″S)-28

¹H-NMR (400 MHz, CDCl₃): δ 9.15 (1H, b, 1′N—H)

δ 8.70 (1H, d, J=3.0, 2′—H)

δ 8.15 (1H, m, 7′—H)

δ 7.43 (3H, m, 4′-6′—H)

δ 7.29 (5H, m, —Ph)

δ 5.43 (2H, dd, J=12.5, 14.6, —CH₂Ph)

δ 4.04 (1H, t, J=7.5, 1′—H)

δ 2.39 (6H, s, N(CH₃)₂)

δ 2.05 (1H, m, 2″—H)

δ 1.84 (1H, m, 2″—H)

δ 1.46 (2H, m, 4″—H)

δ 1.22 (1H, m, 3″—H)

δ 0.89 (3H, d, J=6.6, 6″—H)

δ 0.88 (3H, t, J=7.4. 5″—H)

(1″R, 3″S)-29

IR (KBr): ν [cm⁻¹]=3421, 2962, 1597, 1385, 754

¹H-NMR (400 MHz, CDCl₃): δ 8.67 (1H, s, 2′—H)

δ 8.09 (1H, d, J=7.5, 7′—H)

δ 7.42 (1H d, J=7.6, 4′—H)

δ 7.14 (2H, m, 5′, 6′—H)

δ 3.91 (1H, dd, J6.3, 8.8, 1″—H)

δ 2.36 (6H, s, N(CH₃)₂)

δ 1.96 (2H, m, 2″—H)

δ 1.49 (1H, m, 4″—H)

δ 1.41 (1H, m, 4″—H)

δ 1.21 (1H, m, 3″—H)

δ 0.90 (3H, d, J=6.8, 6″—H)

δ 0.89 (3H, t, J=7.4, 5″—H)

¹³C-NMR (400 MHz, CDCl₃): 163.71 f(s), 160.71(s), 159.13(s), 152.42(s),137.73(s), 131.49(s), 130.10(s), 129.61(s),

123.19(s), 121.60(s), 121.46(s), 112.74(s),

61.99(s), 42.21(s), 42.10(s), 38.74(s), 32.92(s),

29.96(a), 19.78(s), 11.37(s)

EXAMPLE 3 Synthesis of (1″S,3″R)-indole

Similar to Example 1, (1″s,3″R)-indole is prepared from tryptophan esterand (2R,4S)-homoisoleucine in the Preparation Example 3 according to thefollowing synthetic route.

Physical data for respective compounds are shown as follows.

(Compound 39)

¹H-NMR (400 Mhz, CDCl₃): δ 8.02 (1H, b, 1N—H)

δ 7.52 (1H, d, J=7.8, 7—H)

δ 7.21 (9H, m, Aromatic Hs)

δ 6.86 (1H, s, 2—H)

δ 6.54 (1H, b, 1″N—H)

δ 5.06 (2H, s, 4′—H)

δ 4.94 (1H, d, J=7.8, 2′—H)

δ 4.74 (1H, b, 9″—H)

δ 4.10 (1H, b, 3″—H)

δ 3.32 (2H, d, J=4.9, 1′—H)

δ 1.56 (1H, m, 5″—H)

δ 1.46 (9H, s, BOC—HS)

δ 1.26 (1H, t, J=7.0, 4″—H)

δ 1.16 (1H, f, J=70, 4″—H)

δ 0.85 (3H, d, J=6.6, 8″—H)

δ 0.83 (3H, t, J=7.4, 7″—H)

(1″S, 3″R)-40

IR (KBr): ν [cm⁻¹]=3276, 2962, 1685, 1593

(1″S, 3″R)-41

IR (KBr): ν [cm⁻¹]3274, 2958, 1707, 1593

(1″S, 3″R)-42

¹H-NMR (400 MHz, CDCl₃): δ 9.15 (1H, b, 1′N—H)

δ 8.70 (1H, d, J=2.9, 2′—H)

δ 8.16 (1H, m, 7′—H)

δ 7.43 (3H, m, 4′˜6′—H)

δ 7.30 (5H, m, —Ph)

δ 5.43 (2H, dd, J=12.3, 15.2, —CH₂Ph)

δ 4.03 (1H, ?, 1″—H)

δ 2.39 (6H, s, N(CH₃)₂)

δ 2.06 (1H, m, 2″—H)

δ 1.80 (1H, m, 2″—H)

δ 1.50 (1H, m, 4″—H)

δ 1.43 (1H, m, 4″—H)

δ 1.23 (1H, m, 3″—H)

δ 0.89 (3H, d, J=6.6, 6″—H)

δ 0.89 (3H, t, J=7.3, 5″—H)

(1″S, 3″R)-43

IR (KBr) ν [cm⁻¹]=3400, 2960, 1591, 1458, 1389, 744

EXAMPLE 4 Synthesis of (1″R,3″R)-indole

Similar to Example 1, (1″R,3″R)-indole is prepared from tryptophan esterand (2R,4R)-homoisoleucine in the Preparation Example 4 according to thefollowing synthetic route.

EXAMPLE 5 Synthesis of Stereoisomeric Indole Compound From TryptophanEster and L-isoleucine

1. t-Butoxycarbonylation of L-isoleucine (step 1 in Scheme 9)

3.00 mg (22.87 mmol) of L-isoleucine (S)-11 is introduced in a 300 mlegg plant type flask and dissolved by adding 21 ml of 1N-NaOH,Furthermore, 15 ml of water, 15 ml of dioxane and 5.49 mg (25.15 mmol)of Boc₂O are added and stirred at room temperature for 5 hours, andadditional 2.70 mg (12.37 mmol) of Boc₂O are added and stirred at roomtemperature for 13 hours. The reaction solution is washed for threetimes with 30 ml of ether, pH is adjusted to 2-3 by adding citric acidto an aqueous layer in an ice bath, and thereafter it is washed twicewith 50 ml of diethyl ether, extracted twice with 30 ml of ethylacetate, washed for 5 times with 20 ml of water, dried with sodiumsulfate and distilled off the solvent, to obtain 4.69 g (yield; 88.7%)of a Boc form (S)-12 of L-isoleucine as colorless oil.

2. Condensation of tryptophan-O-benzyl ester with Boc form ofL-isoleucine (step 2 in Scheme 9)

After 0.60 g (1.81 mmol) of tryptophan benzyl ester hydrochloride isintroduced in a 100 ml egg plant type flask and argon displacement iscarried out, 30 ml of anhydrous THF is added and stirred. Also, 0.48 g(1.94 mmol) of the Boc form (S)-12 of L-isoleucine is introduced in ananother flask, subjected to argon displacement and dissolved in 10 ml ofanhydrous THF, which is added into the 100 ml egg plant type flask. Itis cooled to 0° C. in an ice bath, and 0.58 ml (3.88 mmol) of acondensing agent, DEPC (diethylphosphoryl cyanide) and 0.60 ml (3.59mmol) of triethylamine are added dropwise, and stirred at 0° C. for 1hour and thereafter at room temperature for 1 hour. 50 ml of ethylacetate is added to the reaction solution, which is washed with anaqueous saturated sodium hydrogencarbonate solution and a saturatedsaline solution, dried with anhydrous sodium sulfate and distilled offthe solvent under a reduced pressure. 1.28 g of the obtained brown oilis purified with a silica gel column (60 g of SiO₂, ethylacetate/hexane=1:2) and thereafter recrystallized from ethyl acetate andhexane, to obtain 888.4 mg (yield; 96.5%) of an intended condensate,dipeptide (S)-13 as white needle crystals.

3. DDQ oxidation of dipeptide (S)-13 (step 3 in Scheme 9)

1.50 g (2.94 mmol) of the condensate, dipeptide (S)-13, is introduced ina 200 ml egg plant type flask, subjected to argon displacement, anddissolved in 75 ml of anhydrous THF by adding said THF thereto. 1.31 g(5.77 mmol) of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) recrystallizedfrom benzene is added and heated at reflux for 3 hours. The solvent ofthe reaction solution is distilled off, and 200 ml of ethyl acetate and20 ml of water are added to the residue to carry out extraction, andthereafter the reaction solution is washed with an aqueous saturatedsodium hydrogencarbonate solution and a saturated saline solution, driedwith anhydrous magnesium sulfate and distilled off the solvent. 1.52 gof the obtained residue is purified with a silica gel column (90 g ofSiO₂, ethyl acetate/hexane=1:3), to obtain 1.46 g (98.3%) of crudecrystals. They are recrystallized from ethyl acetate and n-hexane, toobtain 746.9 mg (50.2%) of an intended cyclized form (S)-14 as whitecrystals.

4. De-t-butoxycarbonylation of cyclized form (S)-14 (step 4 in Scheme 9)

200 mg (0.40 mmol) of the cyclized form (S)-14 is introduced in a 30 mltwo-necked egg plant type flask, dissolved in 5.0 ml (6.49 mmol) ofdichloromethane and cooled to 0° C. with an ice bath, to whichtrifluoroacetjc acid is added and stirred at room temperature until theraw materials being disappeared. The reaction solution is cooled againto 0° C., neutralized with an aqueous saturated sodium hydrogencarbonatesolution, distilled off dichloromethane and extracted with ethylacetate, and thereafter an organic layer is washed with an aqueoussaturated sodium chloride solution, dried with anhydrous sodium sulfateand magnesium sulfate, and distilled off the solvent under a reducedpressure, to obtain 185.6 mg of the residue. It is purified with asilica gel column (15 g of SiO₂, ethyl acetate/hexane=1:3), to obtain143.5 mg (93.3%) of a cyclized form (S)-15, which is furthermorerecrystallized from ethyl acetate and n-hexane, to obtain 109.0 mg(68.0%) of white crystals.

C₂₄H₂₅N₃ O₃ (MW.403.48), mp.137-138° C. [α]_(D) ^(21.5)−41.6 (c=0.58.CHCl₃) IR(KBr) ν [cm⁻¹]=3282, 2962, 1707, 1593, 1458, 1389, 1360, 1281,1244, 1192, 1144, 1074, 958, 744, 698, 418

5. Dimethylation of cyclized form (S)-15 (step 5 in Scheme 9)

298.0 mg (0.74 mmol) of the cyclized form (S)-15 is introduced in a 100ml egg plant type flask and dissolved by adding 14 ml of 37%formaldehyde, 8.0 ml of acetic acid and 6.0 ml of 1,4-dioxane, to which300 mg of 10% Pd-C is added with cooling in an ice bath and thenhydrogen displacement is carried out. Thereafter, the ice bath isremoved and stirring is carried out at room temperature for 2.5 hours.Ethanol is added to the reaction solution, Pd-C is removed byfiltration, and the filtrate is concentrated. 967.7 mg of the residue isobtained, which is purified with a silica gel column (45 g of SiO₂,ethyl acetate/hexane=1:2), to obtain 216.2 mg (yield; 67.9%) of anintended white amorphous dimethyl form (S)-16.

C₂₆H₂₉N₃ O₃, [α]_(D) ¹⁹−60.4 (c=0.33, CHCl₃) IR(KBr) ν [cm⁻¹]=3406,2964, 2931, 2675, 2829, 2783, 1707, 1589, 1458, 1389, 1331, 1281, 1244,1190, 1136, 1074, 958, 744, 698

6. Debenzylzation of dimethyl form (8)-16 (step 6 in Scheme 9)

87.0 mg of the dimethyl form (S)-16 is introduced in a 50 ml egg plantflask and dissolved by adding 4.0 ml of ethyl acetate, to which 170 mgof 10% Pd-C is added with ice cooling, subjected to hydrogendisplacement, and stirred at room temperature for 2 hours. Ethanol isadded to the reaction solution, Pd-C is removed by filtration, and thefiltrate is concentrated, to obtain 64.3 mg (yield; 93.5%) of an almostpure intended compound as powders. Furthermore, dichloromethane is addedto the residue, and insoluble fractions are washed with ethyl ether, toobtain 24.8 mg (yield; 36.0%) of a pure intended compound (S)-17.

C₁₉H₂₃N₃ O₃, [α]_(D) ²⁰−61.0 (c=0.30, MeOH) IR(KBr) ν [cm⁻¹]=3855, 3413,2966, 2927, 2875, 2789, 1601, 1523, 1458, 1396, 1244, 1122, 951, 816,742

II. Synthesis of Deamino Form of Stereoisomeric Compound(deaminomartefragin)

Synthetic examples of deamino forms of the indole compounds according tothe invention are illustrated as follows. Before synthesis of thecompound according to the invention, synthesis of a raw materialthereof, 4-methylhexanoic acid, is illustrated in Preparation Examples 5and 6, and synthetic examples using it are illustrated in Example 6.

In the following description, demino isomers of the indole compounds ofthe formula (1) are denoted as compounds 55 and 56; tryptophan of theformula (2) is denoted as compound 14; 4-methylhexanoic acid of theformula (3) is denoted as the compound S-6, R-32; and the amide formcompound of the formula (4) is denoted as the compound 54.

PREPARATION EXAMPLE 5 Synthesis of Optically Active(S)-4-maethylhexanoic acid (S-6)

Optically active (S)-4-methylhexanoic acid is obtained from an opticallyactive methylbutanol as a raw material by carrying out the Scheme 1 inthe above-mentioned synthetic route of (2S,4S)-homoisoleucine (I.Synthesis for amino forms of indole compounds, Preparation Example 1) tothe reaction step (5).

PREPARATION EXAMPLE 6 Synthesis of Optically Active (R)-4-methylhexanoicacid (R-32)

Optically active (R)-4-methylhexanoic acid is obtained from(S)-citronellol as a raw material by carrying out the Scheme 3 in theabove-mentioned synthetic route of (2S,4R)-homoisoleucine (I. Synthesisfor amino forms of indole compounds, Preparation Example 3) to thereaction step (3).

(S)-4-methylhexanoic acid can be also prepared similar to theabove-mentioned Preparation Example 6, in the case that (R)-citronellolbeing used as a raw material.

Next, synthetic example of indole compounds, deaminomartefragins(compounds 55 and 56) from tryptophan ester (compound 14) and4-methylhexanoic acid (compound S-6) is illustrated.

EXAMPLE 6 Synthesis of Deaminomartefragin

1. Synthesis of compound 54

While (S)-4-methylhexanoic acid (1.0 g, 1.1 equivalents) anddiethylphosphoryl cyanide (DEPC, 2.07 ml, 2.0 equivalents) are added toa solution of L-tryptophan benzyl ester hydrochloride (2.31 g, 7.0 mmol)in THF (100 ml) and stirred at 0° C., triethylamine (2-34 ml, 2.4equivalents) is added and stirred at 0° C. for further 1 hour. Afterconcentrating the reaction solution under a reduced pressure, ethylacetate is added to the residue. The ethyl acetate solution is washed byadding saturated sodium hydrogencarbonate solution and thereafter washedwith 10% hydrochloric acid and a saturated saline solution. An organiclayer is dried with anhydrous sodium sulfate and distilled off thesolvent under a reduced pressure, to obtain a crude product. The crudeproduct is recrystallized from an ethyl acetate:n-hexane mixed solvent(1:1), to obtain a compound 54 (2.54 g, yield: 89%).

C₂₅H₃₀N₂, O₃ (MW.406.23); colorless powder; mp. 80-81° C. (ethylacetate: n-hexane, 1:1) [α]_(D) ²³:−5.03(c=1.09, CHCl₃) IR (neat): ν[cm⁻³]3300 (—NH), 3112, 2959,1732 (—COO),1651(—CONH), 519, 1456, 1379,1354, 741, 697 ¹H-NMR (400 Mhz, CDCl₃): δ 8.59 (1H, broad, 1N—H) 7.53(1H, d, J=7.8, 7—H), 7.21 (9H, m, aromatic-H), 6.74 (1H, d, J=1.7, 2—H),6.12 (1H, d, J=7.8, 1″N—H) 5.09 (2H, dd, J=12.2, 19.5, ′—H), 5.03 (1H,m, 2′—H), 3.32 (2H, dd, J=2.0, 5.4, 1′—H), 2.13 (2H, m, 3″—H), 1.61 (1H,m, 4″—H), 1.38 (1H, m, 4″—H), 1.29 (2H, m, 6″—H), 1.10 (1H, m, 5″—H)0.84(3H, d, J=7.1, 8″—H), 0.82 (3H, t, J=6.2, 7″—H)

2. Synthesis of compound S5 [deamino form of indole compound of theformula (1) wherein R being benzyl group]

The compound 54 (500 mg, 1.23 mmol) is dissolved in THE (50 ml), towhich 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 698 mg, 2.5equivalents) is added and heated at reflux for 1 hour. After thereaction solution is cooled, water is added and TRF is distilled offunder a reduced pressure. Ethyl acetate is added to the obtainedresidue, to carry out extraction. An organic layer is washed with asaturated sodium hydrogencarbonate solution, then with a saturatedsaline solution, and thereafter dried with anhydrous sodium sulfate. Thesolvent is distilled off under a reduced pressure, and the obtainedresidue is purified with a silica gel column chromatography (silica gel,ethyl acetate:n-hexane 1:5), to obtain an almost pure compound 55 (232mg, yield; 47%). The compound 55 is recrystallized furthermore fromethyl acetate.

C₂₅H₂₆N₂O₃ (MW. 402.19); colorless powder mp.138.5-139.5° C. (ethylacetate) [α]_(D) ²³:+7.14 (c=1.00, CHCl₃). IR(neat): ν [cm⁻¹]3323, 2960,1684 (CO), 1604, 1570, 1280, 1246, 1203, 1140, 1076, 785, 746

¹H-NMR (400 MHz, CDCl₃): δ 8.71 (1H, d, J=2.9, 2′—H) 8.59 (1H, broad,1N—H), 8.18-8.13 (1H, m, 7′—H), 7.45(3H, m, 4′, 5′, 6′—H), 7.31(5H, m,—Ph), 5.43 (2H, s, —CH₂ Ph), 2.92 (2H, m, 1″—H), 1.93(1H, m, 2″—H),1.71(1H, m, 2″—H), 14.5 (2H, m, 4″—H), 1.23 (1H, m, 3″—H), 0.96 (3H, d,J=6.5, 6″—H), 0.91 (3H, t, J=7.3, 5″—H)

3. Synthesis of compound 56 [deamino form of indole compound of theformula (1) wherein R being H]

The compound 55 (100 mg, 0.25 mmol) is dissolved in 10 ml of ethylacetate, to which 100 mg of 10% palladium-carbon is added and stirred atroom temperature under a hydrogen atmosphere for 2 hours. Ethanol isadded to the reaction solution, the catalyst is filtrated, andthereafter the filtrate is concentrated under a reduced pressure toobtain a crude product (95.4 mg), which is purified with a columnchromatography (silica gel, ethyl acetate:methanol 10:1) to obtain acompound 56 (53 mg, yield; 69%).

C₁₈H₂₀N₂O₃ (MW. 312.15); colorless powder; mp. 181.0-183.0° C. (hydrousethanol) IR(neat): ν [cm⁻¹]3161, 2960, 1676, 1603, 1560, 1458, 1414,1278, 1130, 1082, 949, 741 ¹H-NMR (400 MHz, CDCl₃): δ 8.64 (1H, s,2′—H), 8.04 (1H, d, J=8.0, 7′-H), 7.42(1H, d, J=7.3, 4′—H),7.20-7.13(2H, m, 5′ and 6′—H), 2.88-2.74(2H, m, 1″—H), 1.90-1.80 (1H, m,2″—H), 1.66-1.57 (1H, m, 2″—H), 1.45-1.34 (2H, m, 4″—H), 1.25-1.13(1H,m, 3″—H), 0.92 (3H, d, J=6.6, 6″—H), 0.87 (3H, t, J=7.2, 5″—H)

III. Biological Activities of Stereoisomeric Indole Compounds EXAMPLE 7Effect of Stereoisomeric Indole Compounds Against Lipid peroxidation ofMicrosome in Rat Liver

(1) Determination of peroxidized lipid

10 μl of microsome fraction (protein concentration; 30-50 mg/ ml)prepared from rat liver and 10 μl of a solution of a compound to betested in ethanol are added to 0.5 ml of 0.1 M Tris hydrochloride buffer(pH7.5) containing 14 mM MgCl₂, which is mixed and preincubated at 37°C. for 5 minutes. Then, 10 μl of 0.2M adenosine diphosphate, 10 μl of 12mM FeSO₄, 40 μl of NADPH reproduced system and distilled water are addedto make 1 m1, mixed and reacted at 37° C. for 10 minutes. After thereaction, 2 ml of a 15% trichloroacetic acid solution containing 0.375%thiobarbituric acid (TBA) and 0.25N hydrochloric acid is added andreacted in a boiling water bath for 15 minutes, and then amounts ofthiobarbituric acid reactive substances including malonic dialdehydeproduced by the reaction are determined from absorption at a wavelengthof 535 nm. Based on these values, a value for inhibitory action againstlipid peroxidation at 50% (IC₅₀ value) is obtained.

(2) Test results

As the result of determination about inhibitory action against lipidperoxidation of respective stereoisomeric indole compounds, (1″S,3″S)-19 in Example 1, (1″R, 3″S)-29 in Example 2, (1″R, 3″R)-53 inExample 4, (1″S, 3″R)-43 in Example 3 and (S)-17 in Example 5, IC₅₀values of homoisoleucine types, (S,S) former (R,S) form, (R,R) form and(S,R) form are 1.07, 1.10, 1.24 and 1.10 μg/ml respectively, as shown inthe following Table. Furthermore, IC₅₀ values of hoinoisoleucine (S)form is 1.89 μg/ml, which means slightly weak activity.

Inhibiting Concentration Compound (IC₅₀ μg/ml) (1″S, 3″S)-19 1.07 (1″R,3″S)-29 1.10 (1″R, 3″R)-53 1.24 (1″5, 3″R)-43 1.10 (S)-17 1.89

EXAMPLE 8

Effect of indole compounds against lipad peroxidation of microsome inrat liver

(1) Determination of peroxidated lipid

It is carried out according to the method described in Example 7.

(2) Test results

Inhibitory action against lipid peroxidation of respective indolecompounds, i.e., deaminomartefragin compound 56) in Example 6 andsynthetic; (1″S, 3″S) Martefragin A (the above-mentioned compound 19),are compared and studied. As the result, IC₅₀ values of and synthetic(1″S, 3″S) Martefragin A are 0.33 μg/m and 1.35 μg/ml respectively, asshown in the following Table, thus deaminomartefragin exhibits strongeractivity.

Inhibiting Concentration Compound (IC₅₀ μg/ml) Deaminomartefragin 0.33(compound 56) Synthetic Martefragin A 1.35 [compound(1″S,3″S)-19]

EFFECT OF THE INVENTION

It becomes possible to obtain various novel indole compounds accordingto the invention by a novel synthetic method comprising condensation oftryptophan with a stereoisomeric α-amino acid or 4-methylhexanoic acidto form an amide form and subsequent oxidative cyclization of the amideform to form an oxazole ring at once. Obtained alkaloids having anindole ring and an oxazole ring have physiological activities such asinhibitory action against lipid peroxidation and they can be utilized asmaterials for pharmaceutics and cosmetics and the like. Furthermore,deamino forms of the indole compounds have higher physiologicalactivities such as inhibitory action against lipid peroxidation than theamino forms.

What is claimed is:
 1. A synthetic stereoisomeric indole compound ofR-form or S-form of the formula (1) or a salt thereof

wherein, Y represents the group

wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkylgroup may be optionally substituted with hydroxyl group, carboxyl group,amino group, methylthio group, mercapto group, guanidyl group,imidazolyl group, or benzyl group), and R₁ and R₂ represent eachindependently hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup or aryl group; or

R represents hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup, aryl group, monovalent metal atom, amine or ammonium; and thesymbol ‘*’ represents a position of an asymmetric carbon atom, providedthat when X is —CH₂—C(CH₃)H—CH₂—CH₃, the compound is not the (1″S,3″S)form.
 2. A synthetic stereoisomeric indole compound of R-form or S-formof the formula (1a) or a salt thereof

wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkylgroup may be optionally substituted with hydroxyl group, carboxyl group,amino group, methylthio group, mercapto group, guanidyl group,imidazolyl group, or benzyl group); R represents hydrogen atom, alkylgroup, aralkyl group, cycloalkyl group, aryl group, monovalent metalatom, amine or ammonium; and R₁ and R₂ represent each independentlyhydrogen atom, alkyl group, aralkyl group, cycloalkyl group or arylgroup and the symbol ‘*’ represents a position of an asymmetric carbonatom, provided that when X is —CH₂—C(CH₃)H—CH₂—CH₃, the compound is notthe (1″S,3″S) form.
 3. A stereoisomeric indole compound of the formula(1b) or a salt therof

wherein, R represents hydrogen atom, alkyl group, aralkyl group,cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium;and the symbol ‘*’ represents a position of an asymmetric carbon atom.4. A process for preparing a stereoisomeric indole compound of theformula (1)

by condensing tryptophan of the formula (2)

with an acid of the formula (3)

to obtain a compound of the formula (4),

and subjecting the compound of the formula (4) to cyclization, wherein,Y represents the group

wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkylgroup may be substituted with hydroxyl group, carboxyl group, aminogroup, methylthio group, mercapto group, guanidyl group, imidazolylgroup or benzyl group), and R₁ and R₂ represent each independentlyhydrogen atom, alkyl group, aralkyl group, cycloalkyl group or arylgroup; or Y represents the group

R represents hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup, aryl group, monovalent metal atom, amine or ammonium; and thesymbol ‘*’ represents a position of an asymmetric carbon atom.
 5. Aprocess for preparing a stereoisomeric indole compound of the formula(1a)

by condensing tryptophan of the formula (2)

with a stereoisomeric α-amino acid of the formula (3a)

to obtain a compound of the formula (4a),

and subjecting the compound of the formula (4a) to cyclization, wherein,X represents alkyl group having 1-5 carbon atom(s) (the alkyl group maybe substituted with hydroxyl group, carboxyl group, amino group,methylthio group, mercapto group, guanidyl group, imidazolyl group orbenzyl group); R represents hydrogen atom, alkyl group, aralkyl group,cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium;R₁ and R₂ represent each independently hydrogen atom, alkyl group,aralkyl group, cycloalkyl group or aryl group; and the symbol ‘*’represents a position of an asymmetric carbon atom.
 6. A process forpreparing a stereoisomeric indole compound of the formula (1b)

by condensing tryptophan of the formula (2)

with an carboxylic acid of the formula (3b)

to obtain a compound of the formula (4b),

and subjecting the compound of the formula (4b) to cyclization, wherein,R represents hydrogen atom, alkyl group, aralkyl group, cycloalkylgroup, aryl group, monovalent metal atom, amine or ammonium; and thesymbol ‘*’ represents a position of an asymmetric carbon atom.
 7. Alipid peroxidation inhibitor comprising as the active ingredient thesynthetic stereoisomeric indole compound or a salt thereof according toclaim
 1. 8. A synthetic stereoisomeric indole compound of R-form orS-form according to claim 2, of the formula

wherein, R represents hydrogen atom, alkyl group, aralkyl group,cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium;and R₁ and R₂ represent each independently hydrogen atom, alkyl group,aralkyl group, cycloalkyl group or aryl group and the symbol ‘*’represents a position of an asymmetric carbon atom, excluding (1″S,3″S)form of said compound.
 9. A lipid peroxidation inhibitor comprising asthe active ingredient the synthetic stereoisomeric indole compound or asalt thereof according to claim
 2. 10. A lipid peroxidation inhibitorcomprising as the active ingredient the synthetic stereoisomeric indolecompound or a salt thereof according to claim
 8. 11. A lipidperoxidation inhibitor comprising as the active ingredient thestereoisomeric indole compound or a salt thereof according to claim 3.12. The synthetic stereoisomeric indole compound of claim 1, where saidcompound is in the (1″S,3″R) form.
 13. The synthetic stereoisomericindole compound of claim 1, where said compound is in the (1″R,3″R)form.
 14. The synthetic stereoisomeric indole compound of claim 1, wheresaid compound is in the (1″R,3″S) form.
 15. The synthetic stereoisomericindole compound of claim 1, where said compound is in the (1″S,3″S)form.
 16. The synthetic stereoisomeric indole compound of claim 2, wheresaid compound is in the (1″S,3″R) form.
 17. The synthetic stereoisomericindole compound of claim 2, where said compound is in the (1″R,3″R)form.
 18. The synthetic stereoisomeric indole compound of claim 2, wheresaid compound is in the (1″R,3″S) form.
 19. The synthetic stereoisomericindole compound of claim 2, where said compound is in the (1″S,3″S)form.